ln addition to its role in the physiology of the female reproductive tract, progesterone also impacts the cardiovascular system. Nonetheless, the specific effects of this steroid hormone in blood vessels remain unclear. The recent generation of mouse models that lack progesterone receptor (PR) have confirmed that vascular function is affected by progesterone, yet a deeper understanding is still lagging and urgently needed considering the questionable effect of hormonal replacement therapy in the amelioration of cardiovascular disease. Using an animal that expresses beta-galactosidase in the PR locus (PRknock-in beta gal) we found that this gene is expressed in both smooth and endothelial cells providing a rationale to pursue a detailed evaluation of PR function in blood vessels. To gain further insight on the role of PR signaling in the vasculature, we generated a transgenic mouse that over and missexpresses PR in the endothelium of several vascular beds. Systemic treatment with progesterone resulted in pathological vascular permeability in the subset of organs that expressed the transgene. This unexpected finding was in accordance with some phenotypic aspects of the PRKO mouse, which failed to mount an endometrial decidual response upon stimulation with hormones. The decidual response includes concrete alterations in endometrial glands, stromal differentiation, and vascular permeability. Further investigation using endothelial cultures revealed that PR promotes fundamental changes in inter-endothelial junctional complexes. The signaling events mediated by PR appear to be non-genomic in nature and dependent, at least partially, on the ability of PR to directly activate src. In this application, we propose three aims to directly test the hypotheses that progesterone receptor signaling on endothelial cells mediates vascular permeability and formation of intercellular gaps. Specifically we will: (1) Further characterize the effect of progesterone receptor activation on endothelial cells; (2) investigate the molecular mechanisms that mediate progesterone-induced vascular permeability; and (3) determine the biological significance of progesterone receptor signaling in the endothelium and smooth muscle using cell-specific gene ablation. We believe that further elucidation of the role of PR on blood vessels is long overdue and required to gain a concrete understanding of the physiological and pathological effects of this hormone in the cardiovascular system.